High‐mobility group AT‐Hook 1 mediates the role of nuclear factor I/X in osteogenic differentiation through activating canonical Wnt signaling

Stem Cells ◽  
2021 ◽  
Vol 39 (10) ◽  
pp. 1349-1361
Author(s):  
Xiaowen Wu ◽  
Xiaochen Wang ◽  
Liying Shan ◽  
Jie Zhou ◽  
Xin Zhang ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Osteogenic Differentiation ◽  
High Mobility ◽  
High Mobility Group ◽  
Nuclear Factor ◽  
Canonical Wnt Signaling ◽  
Factor I ◽  
Nuclear Factor I ◽  
Canonical Wnt

Nuclear factor I‐C reciprocally regulates adipocyte and osteoblast differentiation via control of canonical Wnt signaling

2017 ◽  
Vol 31 (5) ◽  
pp. 1939-1952 ◽  
Author(s):  
Jie Zhou ◽  
Shan Wang ◽  
Qi Qi ◽  
Xiaoyue Yang ◽  
Endong Zhu ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Osteoblast Differentiation ◽  
Nuclear Factor ◽  
Canonical Wnt Signaling ◽  
Factor I ◽  
Nuclear Factor I ◽  
Canonical Wnt

scholarly journals The Role of Canonical Wnt Signaling in Regulating Radioresistance

2018 ◽  
Vol 48 (2) ◽  
pp. 419-432 ◽  
Author(s):  
Yuanyuan Zhao ◽  
Leilei Tao ◽  
Jun Yi ◽  
Haizhu Song ◽  
Longbang Chen
Keyword(s):  
Wnt Signaling ◽  
Cancer Progression ◽  
Wnt Signaling Pathway ◽  
Growth Factor Receptor ◽  
Cancer Resistance ◽  
Canonical Wnt Signaling ◽  
Damage Repair ◽  
Epidermal Growth ◽  
Canonical Wnt

Radioresistance is a major obstacle in radiotherapy for cancer, and strategies are needed to overcome this problem. Currently, radiotherapy combined with targeted therapy such as inhibitors of phosphoinosotide 3-kinase/Akt and epidermal growth factor receptor signaling have become the focus of studies on radiosensitization. Apart from these two signaling pathways, which promote radioresistance, deregulation of Wnt signaling is also associated with the radioresistance of multiple cancers. Wnts, as important messengers in the tumor microenvironment, are involved in cancer progression mainly via canonical Wnt signaling. Their role in promoting DNA damage repair and inhibiting apoptosis facilitates cancer resistance to radiation. Thus, it seems reasonable to target Wnt signaling as a method for overcoming radioresistance. Many small-molecule inhibitors that target the Wnt signaling pathway have been identified and shown to promote radiosensitization. Therefore, a Wnt signaling inhibitor may help to overcome radioresistance in cancer therapy.

The role of magnesium ions in bone regeneration involves the canonical Wnt signaling pathway

2019 ◽  
Vol 98 ◽  
pp. 246-255 ◽  
Author(s):  
Chu-Chih Hung ◽  
Amy Chaya ◽  
Kai Liu ◽  
Konstantinos Verdelis ◽  
Charles Sfeir
Keyword(s):  
Wnt Signaling ◽  
Bone Regeneration ◽  
Signaling Pathway ◽  
Wnt Signaling Pathway ◽  
Magnesium Ions ◽  
Canonical Wnt Signaling ◽  
Canonical Wnt

scholarly journals Hepatocyte nuclear factor 1β suppresses canonical Wnt signaling through transcriptional repression of lymphoid enhancer–binding factor 1

2020 ◽  
Vol 295 (51) ◽  
pp. 17560-17572
Author(s):  
Siu Chiu Chan ◽  
Sachin S. Hajarnis ◽  
Sophia M. Vrba ◽  
Vishal Patel ◽  
Peter Igarashi
Keyword(s):  
Wnt Signaling ◽  
Transcriptional Repression ◽  
Target Genes ◽  
Regulatory Elements ◽  
Nuclear Factor ◽  
Hepatocyte Nuclear Factor ◽  
Canonical Wnt Signaling ◽  
H3k27 Trimethylation ◽  
Binding Factor ◽  
Canonical Wnt

Hepatocyte nuclear factor-1β (HNF-1β) is a tissue-specific transcription factor that is required for normal kidney development and renal epithelial differentiation. Mutations of HNF-1β produce congenital kidney abnormalities and inherited renal tubulopathies. Here, we show that ablation of HNF-1β in mIMCD3 renal epithelial cells results in activation of β-catenin and increased expression of lymphoid enhancer–binding factor 1 (LEF1), a downstream effector in the canonical Wnt signaling pathway. Increased expression and nuclear localization of LEF1 are also observed in cystic kidneys from Hnf1b mutant mice. Expression of dominant-negative mutant HNF-1β in mIMCD3 cells produces hyperresponsiveness to exogenous Wnt ligands, which is inhibited by siRNA-mediated knockdown of Lef1. WT HNF-1β binds to two evolutionarily conserved sites located 94 and 30 kb from the mouse Lef1 promoter. Ablation of HNF-1β decreases H3K27 trimethylation repressive marks and increases β-catenin occupancy at a site 4 kb upstream to Lef1. Mechanistically, WT HNF-1β recruits the polycomb-repressive complex 2 that catalyzes H3K27 trimethylation. Deletion of the β-catenin–binding domain of LEF1 in HNF-1β–deficient cells abolishes the increase in Lef1 transcription and decreases the expression of downstream Wnt target genes. The canonical Wnt target gene, Axin2, is also a direct transcriptional target of HNF-1β through binding to negative regulatory elements in the gene promoter. These findings demonstrate that HNF-1β regulates canonical Wnt target genes through long-range effects on histone methylation at Wnt enhancers and reveal a new mode of active transcriptional repression by HNF-1β.

scholarly journals Organization of the α-Globin Promoter and Possible Role of Nuclear Factor I in an α-Globin-inducible and in a Noninducible Cell Line

1995 ◽  
Vol 270 (33) ◽  
pp. 19643-19650 ◽  
Author(s):  
Theo Rein ◽  
Reinhold Förster ◽  
Anja Krause ◽  
Ernst-L. Winnacker ◽  
Haralabos Zorbas
Keyword(s):  
Cell Line ◽  
Nuclear Factor ◽  
Factor I ◽  
Nuclear Factor I ◽  
Globin Promoter

Expression of Wnt-3a in Myeloma Cells Inhibits the Osteolytic Phenotype In-Vivo.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3420-3420
Author(s):  
Ya-Wei Qiang ◽  
Shmuel Yaccoby ◽  
John D. Shaughnessy
Keyword(s):  
Bone Resorption ◽  
Wnt Signaling ◽  
Myeloma Cell ◽  
Beta Catenin ◽  
Canonical Wnt Signaling ◽  
Myeloma Cell Line ◽  
Myeloma Cells ◽  
Canonical Wnt

Wnt signaling is a highly conserved signal transduction pathway involved in embryonic development. Inappropriate canonical Wnt signaling resulting in beta-catenin stabilization, is associated with several types of human cancers. Multiple myeloma plasma cells express Wnt receptors, Wnt ligands and soluble Wnt inhibitors. Wnt signaling is central to osteoblast and osteoclasts development and secretion of Wnt signaling inhibitors by myeloma cells is thought to contribute to the osteolytic phenotype seen in this disease and prostate cancer. While it is now clear that MM cells can signal through both canonical and non-canonical mechanisms, there are conflicting data as to the direct role of Wnt signaling in myeloma cell biology. Others have shown that Wnts cause proliferation of myeloma cells; while we have shown that canonical Wnts cause morphological changes and migration, but not cell proliferation. To further elucidate the role of canonical Wnt signaling in myeloma and myeloma bone disease we used limiting dilutions in the presence of G418 to create two independent stable clones of the myeloma cell line NCI-H929 expressing Wnt-3A (H929/W3A), which is not expressed in myeloma, and an empty vector (H929/EV). Because Wnt antibodies are not available we cloned Wnt-3A as a fusion protein with hemagglutinin (HA). Western blots against HA revealed a positive band of the expected size only in the H929/W3A clones. GST-E-cadherin binding assay and Western blot analysis revealed elevated levels of total and free beta-catenin in H929/W3A relative to H929/EV, however, there this was not associated with increased growth or proliferation by MTT assay. To determine the in-vivo growth characteristics and effects on bone resorption of Wnt-3A producing cells, we transplanted the lines into a human bone implanted the flank of SCID mice. Tumor growth rate as determined by increased production of human immunoglobulin in mice serum was significantly slower in the Wnt-3A transfected cells relative to controls (P < .05). Loss of bone mineral density (BMD) of the implanted bones engrafted with H929/W3A cells was lower than in bones engrafted with H929/EV cells (P < .05). Reduced tumor burden and BMD loss was also visualized on x-ray radiographs. Taken together these data indicate that all factors promoting bone resorption produced by or elicited by the myeloma cell line H929 are subordinate to canonical Wnt signaling and that prevention of bone destruction may help control myeloma progression.

Activation of Non-Canonical Wnt Pathway in Human Mesenchymal Cells Affects Osteogenic Differentiation: A Potential Target in Multiple Myeloma Microenvironment

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2742-2742 ◽  
Author(s):  
Nicola Giuliani ◽  
Simona Colla ◽  
Paola Storti ◽  
Gaetano Donofrio ◽  
Marina Bolzoni ◽  
...  
Keyword(s):  
Alkaline Phosphatase ◽  
Wnt Signaling ◽  
Osteogenic Differentiation ◽  
Wnt Signaling Pathway ◽  
Inhibitory Effect ◽  
Canonical Wnt Signaling ◽  
Wnt Pathways ◽  
Canonical Wnt ◽  
Wnt Signal ◽  
Alkaline Phosphatase Expression

Abstract Osteoblast suppression is the hallmark of Multiple Myeloma (MM) osteolytic bone lesions mainly due to the capacity of MM cells to inhibit the osteogenic differentiation of bone marrow (BM) mesenchymal cells (MSC). Many evidences suggest that Wnt signaling is critically involved in the regulation of osteoblast formation. Recently, in murine osteoprogenitor cells and in MM mouse models it has been shown that activation of canonical Wnt pathway stimulate osteoblast formation and blunts MM-induced bone destruction. In this study we have investigated whether modulation of both canonical and noncanonical Wnt signaling pathway may affect osteogenic differentiation of human MSC and counterbalance the suppressive effect of MM cells. First we checked the potential expression of Wnt activators and inhibitors by human MSC and osteoprogenitor cells (PreOB) by gene arrays. We found that both cells expressed the activator of non-canonical Wnt pathways Wnt5a but lack of express the main activators of canonical Wnt signaling as Wnt1, Wnt3a and Wnt8. The presence of the Wnt5a receptor FZD2 and FZD5 was also detected in both cells as well as that of FZD3, FZD6 and FDZ7 and the Wnt canonical co-receptors LRP5 and LRP6. On the other hand we found that both inhibitors of canonical and non-canonical Wnt pathways DKK-1 and sFRP-1 were expressed by MSC. Secondly, activation of either canonical or non-canonical Wnt signaling pathway by Wnt3a and Wnt5a treatment respectively was performed in human MSC to evaluate the effect on osteogenic differentiation and the expression of osteoblast related markers (Collagen I, Osteocalcin and Alkaline Phosphatase). We found that Wnt5a treatment but not Wnt3a significantly increased the early osteogenic differentiation and the expression of alkaline phosphatase in MSC. Consistently in a co-culture system with MM cells Wnt5a treatment blunted, at least in part, the inhibitory effect of MM cells on alkaline phosphatase expression by MSC and PreOB. To go further inside, we evaluated in both primary human BM MSC and the human MSC cell line HS-5 the effect of either the activation of non-canonical Wnt signaling by Wnt5a overexpression using a lentivirus vector or the Wnt5a suppression using siRNA. Wnt5a over-expression in MSC induced the activation of Wnt/Ca++ non-canonical pathway as demonstrated by the increase of Wnt5a secretion and phospho-PKC expression detected by westernblot analysis. Consequently to non-canonical Wnt signal activation we found a significant increase of alkaline phosphatase expression by MSC cells as well as of their osteogenic differentiation. Interestingly, analyzing the gene expression profile by microarray, we found that Wnt5a overexpression in MSC also affects the expression of chemokines, inflammatory cytokines and pro-angiogenic molecules. In conclusion our data indicate that activation of non-canonical Wnt signal pathway may represent a potential target in MM microenvironment to counterbalance the inhibitory effect of MM cells on osteogenic differentiation of human MSC.

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